Many potent and specific peptides suffer problems of short or sub-optimal duration. A possible solution to such problems involves conjugation to macromolecules such as polyethylene glycol (PEG) that are slowly eliminated from the body, and thus prolongs the action of the attached peptide. For peptide therapeutics, it is usually essential that the unchanged drug be released from the macromolecule with timing appropriate to satisfy the need. Current approaches often use cleavable linkers to attach the peptide to the macromolecule by a linker that cleaves because of the effect of an enzyme, or physiological environment. Although such approaches are often successful, they usually do not allow prediction or control of the rate of drug release and hence the duration of action. The objective of this project is a) to develop a novel platform technology that allows site-specific attachment of a macromolecule to peptides, and b) to develop technology for predictable, chemically-controlled release of such peptides. If successful, a) we will have developed general technology for controlled release of peptides from macromolecules that could be broadly applied, and set the stage for future applications of such technology to therapeutic peptides. PUBLIC HEALTH RELEVANCE: We propose to develop a novel platform technology that allows site-specific attachment of macromolecules to peptides, and predictable, controlled release of the native peptides that will allow an increase in the duration of their action. If successful, we will have developed general technology for controlled release of therapeutic peptides from macromolecules that could be broadly applied to the area of therapeutic peptides.